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  Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers

Arumughan, A., Roske, Y., Barth, C., Forero, L. L., Bravo-Rodriguez, K., Redel, A., et al. (2016). Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers. Nature Communications, 7: 7:13047. doi:10.1038/ncomms13047.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-2422-C Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-2423-A
Genre: Journal Article

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 Creators:
Arumughan, Anup , Author
Roske, Yvette , Author
Barth, Carolin , Author
Forero, Laura Lleras, Author
Bravo-Rodriguez, Kenny, Author
Redel, Alexandra , Author
Kostova, Simona , Author
McShane, Erik , Author
Robert Opitz, Robert , Author
Faelber, Katja , Author
Rau, Kirstin, Author
Mielke, Thorsten1, Author              
Daumke, Oliver , Author
Selbach, Matthias , Author
Sanchez-Garcia, Elsa, Author
Rocks, Oliver , Author
Daniela Panáková, Daniela , Author
Heinemann, Udo, Author
Wanker, Erich E., Author
Affiliations:
1Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              

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Free keywords: ER-associated degradation; Nucleotide-binding proteins; X-ray crystallography
 Abstract: Interaction mapping is a powerful strategy to elucidate the biological function of protein assemblies and their regulators. Here, we report the generation of a quantitative interaction network, directly linking 14 human proteins to the AAA+ ATPase p97, an essential hexameric protein with multiple cellular functions. We show that the high-affinity interacting protein ASPL efficiently promotes p97 hexamer disassembly, resulting in the formation of stable p97:ASPL heterotetramers. High-resolution structural and biochemical studies indicate that an extended UBX domain (eUBX) in ASPL is critical for p97 hexamer disassembly and facilitates the assembly of p97:ASPL heterotetramers. This spontaneous process is accompanied by a reorientation of the D2 ATPase domain in p97 and a loss of its activity. Finally, we demonstrate that overproduction of ASPL disrupts p97 hexamer function in ERAD and that engineered eUBX polypeptides can induce cell death, providing a rationale for developing anti-cancer polypeptide inhibitors that may target p97 activity.

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Language(s): eng - English
 Dates: 2016-02-162016-08-292016-10-20
 Publication Status: Published online
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/ncomms13047
 Degree: -

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 7 Sequence Number: 7:13047 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: /journals/resource/2041-1723